A factor leading to development of vascular disease, a leading cause of death in industrialized nations, is elevated serum cholesterol. It is estimated that 19% of Americans between the ages of 20 and 74 years of age have high serum cholesterol. Blood cholesterol levels correlate to a risk of developing atherosclerosis and coronary heart disease, which creates an increased danger of heart attacks and strokes.
Due to the insolubility of cholesterol, blood transports cholesterol in a modified form of lipoproteins. Two primary forms of the lipoproteins include low-density lipoprotein (LDL), also known as “bad” cholesterol, and high-density lipoprotein (HDL), also known as “good” cholesterol. HDL cholesterol is beneficial largely because of its ability to perform reverse cholesterol transport, i.e. to scavenge excess cholesterol from arteries and deposit it in the liver for clearance through biliary excretion. See Zannis et al., J Mol. Med. 84(4):276-94 (2006), Lewis et al., Circ Res. 96(12):1221-32 (2005) and Tall et al., Arterioscler. Thromb. Vasc. Biol. 20(5):1185-8 (2000). HDL also exhibits other anti-inflammatory and antioxidant properties. See Barter et al., Circ Res. 95(8):764-72 (2004).
HDL is the smallest (7.0-12 nm diameter) and densest of the plasma lipoproteins. It consists of a hydrophobic core composed mainly of cholesteryl esters plus a small amount of triglyceride (TG) and unesterified cholesterol surrounded by a surface monolayer of phospholipids, unesterified cholesterol and apolipoproteins. The main HDL apolipoproteins (apo) are apoAI and apoAII. See Zannis et al., J Mol. Med. 84(4):276-94 (2006) and Lewis et al., Circ Res. 96(12):1221-32 (2005).
There are currently no drugs on the market that act directly on the reverse cholesterol pathway. See Ashen et al., N Enql J. Med. 353(12):1252-60 (2005). Pathways targeted by industry to increase HDL have been to increase synthesis and secretion of apoA1, and/or to decrease HDL catabolism. Several known agents called fibrates (e.g. Gemfibrozil) increase HDLc levels by acting on the liver. See Linsel-Nitschke et al., Nat Rev Druq Discov. 4(3): 193-205 (2005).
NRIP1, (Nuclear Receptor Interacting Protein 1, also known as RIP140), is a to corepressor that can inhibit the transcriptional activity of a number of nuclear receptors that influence such diverse processes as muscle metabolism, adipocyte and hepatocyte function, and reproduction. See, e.g., White et al., FEBS Lett. 582:39-45 (2008); Augereau et al., J. Steroid Biochem. & Mol. Biol. 102:51-59 (2006).